Reduced Temperature Sterilization of Stents

ABSTRACT

Methods and systems for reduced temperature radiation sterilization of stents are disclosed.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to radiation sterilization of stents.

2. Description of the State of the Art

This invention relates to radially expandable endoprostheses, which areadapted to be implanted in a bodily lumen. An “endoprosthesis”corresponds to an artificial device that is placed inside the body. A“lumen” refers to a cavity of a tubular organ such as a blood vessel.

A stent is an example of such an endoprosthesis. Stents are generallycylindrically shaped devices, which function to hold open and sometimesexpand a segment of a blood vessel or other anatomical lumen such asurinary tracts and bile ducts. Stents are often used in the treatment ofatherosclerotic stenosis in blood vessels. “Stenosis” refers to anarrowing or constriction of the diameter of a bodily passage ororifice. In such treatments, stents reinforce body vessels and preventrestenosis following angioplasty in the vascular system. “Restenosis”refers to the reoccurrence of stenosis in a blood vessel or heart valveafter it has been treated (as by balloon angioplasty, stenting, orvalvuloplasty) with apparent success.

The treatment of a diseased site or lesion with a stent involves bothdelivery and deployment of the stent. “Delivery” refers to introducingand transporting the stent through a bodily lumen to a region, such as alesion, in a vessel that requires treatment. “Deployment” corresponds tothe expanding of the stent within the lumen at the treatment region.Delivery and deployment of a stent are accomplished by positioning thestent about one end of a catheter, inserting the end of the catheterthrough the skin into a bodily lumen, advancing the catheter in thebodily lumen to a desired treatment location, expanding the stent at thetreatment location, and removing the catheter from the lumen.

In the case of a balloon expandable stent, the stent is mounted about aballoon disposed on the catheter. Mounting the stent typically involvescompressing or crimping the stent onto the balloon. The stent is thenexpanded by inflating the balloon. The balloon may then be deflated andthe catheter withdrawn. In the case of a self-expanding stent, the stentmay be secured to the catheter via a retractable sheath or a sock. Whenthe stent is in a desired bodily location, the sheath may be withdrawnwhich allows the stent to self-expand.

The stent must be able to satisfy a number of mechanical requirements.First, the stent must be capable of withstanding the structural loads,namely radial compressive forces, imposed on the stent as it supportsthe walls of a vessel. Therefore, a stent must possess adequate radialstrength. Radial strength, which is the ability of a stent to resistradial compressive forces, is due to strength and rigidity around acircumferential direction of the stent. Radial strength and rigidity,therefore, may also be described as, hoop or circumferential strengthand rigidity.

Once expanded, the stent must adequately maintain its size and shapethroughout its service life despite the various forces that may come tobear on it, including the cyclic loading induced by the beating heart.For example, a radially directed force may tend to cause a stent torecoil inward. Generally, it is desirable to minimize recoil.

In addition, the stent must possess sufficient flexibility to allow forcrimping, expansion, and cyclic loading. Longitudinal flexibility isimportant to allow the stent to be maneuvered through a tortuousvascular path and to enable it to conform to a deployment site that maynot be linear or may be subject to flexure. Finally, the stent must bebiocompatible so as not to trigger any adverse vascular responses.

The structure of a stent is typically composed of scaffolding thatincludes a pattern or network of interconnecting structural elementsoften referred to in the art as struts or bar arms. The scaffolding canbe formed from wires, tubes, or sheets of material rolled into acylindrical shape. The scaffolding is designed so that the stent can beradially compressed (to allow crimping) and radially expanded (to allowdeployment). A conventional stent is allowed to expand and contractthrough movement of individual structural elements of a pattern withrespect to each other.

Additionally, a medicated stent may be fabricated by coating the surfaceof either a metallic or polymeric scaffolding with a polymeric carrierthat includes an active or bioactive agent or drug. Polymericscaffolding may also serve as a carrier of an active agent or drug.

After a stent is fabricated, a stent typically undergoes sterilizationto reduce the bioburden of the stent to an acceptable sterilityassurance level (SAL). There are numerous methods of sterilizing medicaldevices such as stents, the most common being ethylene oxide treatmentand treatment with ionization radiation such as electron beam and gammaradiation. Generally, it is desirable for the sterilization procedure tohave little or no adverse affects on the material properties of thestent.

SUMMARY

Certain embodiments of the present invention are directed to a method ofsterilizing a stent comprising: cooling a stent to a sterilizationtemperature below ambient temperature; and exposing the cooled stent toa dose of radiation.

Additional embodiments of the present invention are directed to a methodof sterilizing a stent comprising: cooling a stent to a sterilizationtemperature below ambient temperature; exposing the stent to a dose ofradiation; and cooling the stent during the exposure to maintain thetemperature of the stent during exposure at less than a selectedtemperature.

Further embodiments of the present invention are directed to a systemfor packaging a stent comprising: a container capable of storing astent; a stent disposed within the container; and a cold medium disposedwithin the container adjacent to the stent, the cold media capable ofreducing and maintaining the temperature of the stent below ambienttemperature.

Some embodiments of the present invention are directed to a method forpackaging a stent comprising: disposing a stent in a container forstoring the stent, wherein a cold medium is disposed within thecontainer, the cold medium reducing and maintaining the temperature ofthe stent below ambient temperature; and exposing the stent to a dose ofradiation to sterilize the stent.

Additional embodiments of the present invention are directed to a methodof sterilizing a stent comprising: selectively conveying a cooling fluidat or adjacent to a stent to reduce the temperature of the stent to asterilization temperature below an ambient temperature; and directing adose of radiation at the cooled stent.

Other embodiments of the present invention are directed to a method ofsterilizing a stent comprising: disposing a stent in a container;disposing a cooling medium adjacent to the stent to reduce and/ormaintain a temperature of the stent in the container at a sterilizationtemperature that is below ambient temperature; and directing a dose ofradiation at the container to sterilize the stent.

Further embodiments of the present invention are directed to a method ofsterilizing a stent comprising: cooling a stent to a sterilizationtemperature below an ambient temperature; and directing a dose ofradiation from a radiation source at the cooled stent, a radiationbarrier between the stent and the radiation source selectively reducingthe radiation exposure of the stent.

Additional embodiments of the present invention are directed to a systemof sterilizing a stent comprising: a hollow ring-shaped conduitincluding a plurality of holes for disposing a stent; a cooling mediumwithin the conduit for maintaining the temperature of a stent disposedthrough one of the holes within the conduit in a sterilizationtemperature range; and a radiation source capable of exposing theconduit to a dose of radiation as the conduit is translated through theradiation source, the source being capable of exposing the stent toradiation.

Further embodiments of the present invention are directed to a method ofsterilizing a stent comprising: disposing a stent on or adjacent to asurface of a cooling member, wherein the cooling member maintains atemperature of the stent at a sterilization temperature below ambienttemperature before, during, and/or after exposing the stent toradiation; and directing a dose of radiation at the stent, the stentbeing positioned between the cooling slab and the radiation source.

Other embodiments of the present invention are directed to a system forsterilizing a stent comprising: a cooling member capable of maintaininga temperature of a stent at a sterilization temperature below ambienttemperature before, during, and/or after exposing the stent toradiation, wherein the stent is positioned on or adjacent to a surfaceof the cooling member; and a radiation source for exposing the stern toradiation to sterilize the stent, the stent being positioned between thecooling member and the radiation source.

Additional embodiments of the present invention are directed to methodof sterilizing a stent comprising: disposing a stent adjacent to asurface of a cooling member; conveying a cooling fluid from the surfaceof the cooling member, wherein the cooling fluid facilitates maintaininga temperature of the stent at a sterilization temperature below ambienttemperature before, during, and/or after exposing the stent toradiation; and directing a dose of radiation at the stent, the stentbeing positioned between the cooling member and the radiation source.

Some embodiments of the present invention are directed to a system forsterilizing a stent comprising: a cooling member including a coolingmedium disposed in cavity of the cooling medium, the surface of thecooling member having a plurality of holes in communication with thecavity, the holes for conveying a cooling fluid from the surface of thecooling member, the cooling fluid facilitating maintaining a temperatureof a stent disposed at or adjacent to the surface of the cooling memberat a sterilization temperature below ambient temperature before, during,and/or after exposing the stent to radiation; and a radiation source forexposing the stent to radiation, the stent being positioned between thecooling member and the radiation source.

Certain embodiments of the present invention are directed to a systemfor sterilizing a stent comprising: a stent disposed in a storagecontainer, the storage container being disposed within a cavity of abody of thermal insulating material; a cold medium disposed adjacent tothe storage container within the cavity to cool the stent; and aradiation source for directing radiation at the stent to sterilize thestent.

Further embodiments of the present invention are directed to a method ofsterilizing a stent comprising: disposing a storage container containinga stent within a cavity of a body a thermal insulating material, whereina cold medium is disposed adjacent to the storage container within thecavity to cool the stent; and directing radiation at the stent.

Other embodiments of the present invention are directed to a system forsterilizing a stent comprising: a stent disposed in a storage container,the container including a sealed storage region including the stent anda cooling region adjacent to the storage region, the cooling regionincluding a cold medium for reducing and maintaining the temperature ofthe stent below an ambient temperature.

Further embodiments of the present invention are directed to a method ofsterilizing a stent comprising: directing radiation at a stent in astorage container, the container including a sealed storage regionincluding the stent and a cooling region adjacent to the storage region,the cooling region including a cold medium for reducing and maintainingthe temperature of the stent below an ambient temperature.

Some embodiments of the present invention are directed to a system forsterilizing a stent comprising: a cooling container comprising a coolingregion and a sleeve adjacent to the cooling region, the cooling regionincluding a cold medium; and a sealed stent storage container includinga stent, the container disposed in the sleeve, the cold medium reducesand maintains the temperature of the stent below an ambient temperature.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a stent.

FIG. 2 depicts a radiation sterilization system.

FIG. 3 depicts a stent-catheter assembly.

FIGS. 4A-C depict embodiments for selective cooling of a stent.

FIGS. 5A-D depict an exemplary embodiment of a system for reducedtemperature radiation sterilization of a stent.

FIGS. 6A-C depict an exemplary embodiment of a system for reducedtemperature radiation sterilization of a stent.

FIG. 7 depicts an exemplary embodiment of a system for reducedtemperature radiation sterilization of a stent.

FIG. 8 depicts an exemplary section of the conduit from FIG. 5A.

FIG. 9A-C depict an exemplary system for reduced temperaturesterilization of a stent.

FIG. 10A-B depict a stent catheter assembly disposed in a sealedflexible storage container.

FIG. 11A-B depict a storage container for a stent that includes a coldmedium pocket.

FIG. 12A-B depict a storage container for a stent with a sleeve adaptedto receive a cold medium pocket.

FIG. 13A-B depict a cold medium storage container having a cold mediumregion and a sleeve adapted to receive a stent storage container.

FIG. 14 is a graph depicting the number of cracks in irradiated deployedstents.

DETAILED DESCRIPTION OF THE INVENTION

Various embodiments of the present invention relate to sterilizingstents, that are made in whole or in part of polymers, with radiation atreduced temperatures. The reduced temperature of the stent tends tofacilitate preservation of the material properties of the polymer in thestent during and after exposure to radiation.

The method and systems described herein may be may be applied generallyto implantable medical devices. The methods and systems are particularlyrelevant, for reasons discussed below, to implantable medical deviceshaving a polymeric substrate, a polymer-based coating, and/or adrug-delivery coating. A polymer-based coating may contain, for example,an active agent or drug for local administration at a diseased site. Animplantable medical device may include a polymer or non-polymersubstrate with a polymer-based coating.

Examples of implantable medical devices include self-expandable stents,balloon-expandable stents, stent-grafts, grafts (e.g., aortic grafts),artificial heart valves, cerebrospinal fluid shunts, pacemakerelectrodes, and endocardial leads (e.g., FINELINE and ENDOTAK, availablefrom Guidant Corporation, Santa Clara, Calif.). The underlying structureor substrate of the device can be of virtually any design.

The structure of a stent in particular can have a scaffolding or asubstrate that includes a pattern of a plurality of interconnectingstructural elements or struts. FIG. 1 depicts an example of a view of astent 100. Stent 100 has a cylindrical shape and includes a pattern witha number of interconnecting structural elements or struts 110. Ingeneral, a stent pattern is designed so that the stent can be radiallycompressed (crimped) and radially expanded (to allow deployment). Thestresses involved during compression and expansion are generallydistributed throughout various structural elements of the stent pattern.The present invention is not limited to the stent pattern depicted inFIG. 1. The variation in stent patterns is virtually unlimited.

A stent such as stent 100 may be fabricated from a polymeric tube or asheet by rolling and bonding the sheet to form a tube. A stent patternmay be formed on a polymeric tube by laser cutting a pattern on thetube. Representative examples of lasers that may be used include, butare not limited to, excimer, carbon dioxide, and YAG. In otherembodiments, chemical etching may be used to form a pattern on a tube.

A stent has certain mechanical requirements that are crucial tosuccessful treatment. For example, a stent must have sufficient radialstrength to withstand structural loads, namely radial compressiveforces, imposed on the stent as it supports the walls of a vessel. Inaddition, the stent must possess sufficient flexibility to allow forcrimping, expansion, and cyclic loading. Bending elements 130, 140, and150, in particular, are subjected to a great deal of stress and strainduring use of a stent.

It is well known by those skilled in the art that the mechanicalproperties of a polymer can be modified by applying stress to a polymer.The strength and modulus of a polymer tend to be increased along thedirection of the applied stress. The application of stress can inducemolecular orientation along the direction of stress which can increasethe strength and modulus along the direction. Molecular orientationrefers to the relative orientation of polymer chains along alongitudinal or covalent axis of the polymer chains.

Therefore, in some embodiments, a polymer tube can be radially deformedprior to laser cutting to enhance radial strength. The radialdeformation increases the strength and modulus in the circumferentialdirection. The increase in strength and modulus can be due to theinduced molecular orientation in the circumferential direction. However,as the temperature of the polymer increases close to or above Tg, someor all of the induced orientation and strength can be lost due torelaxation of polymer chains.

Sterilization is typically performed on medical devices, such as stents,to reduce the bioburden on the device. Bioburden refers generally to thenumber of microorganisms with which an object is contaminated. Thedegree of sterilization is typically measured by a sterility assurancelevel (SAL) which refers to the probability of a viable microorganismbeing present on a product unit after sterilization. The required SALfor a product is dependent on the intended use of the product. Forexample, a product to be used in the body's fluid path is considered aClass III device. SAL's for various medical devices can be found inmaterials from the Association for the Advancement of MedicalInstrumentation (AAMI) in Arlington, Va.

Radiation sterilization is well known to those of ordinary skill theart. Medical devices composed in whole or in part of polymers can besterilized by various kinds of radiation, including, but not limited to,electron beam (e-beam), gamma ray, ultraviolet, infra-red, ion beam,x-ray, and laser sterilization. A sterilization dose can be determinedby selecting a dose that provides a required SAL. A sample can beexposed to the required dose in one or multiple passes.

However, it is known that radiation can alter the properties of thepolymers being treated by the radiation. High-energy radiation tends toproduce ionization and excitation in polymer molecules. Theseenergy-rich species undergo dissociation, abstraction, and additionreactions in a sequence leading to chemical stability. The stabilizationprocess can occur during, immediately after, or even days, weeks, ormonths after irradiation which often results in physical and chemicalcross-linking or chain scission. Resultant physical changes can includeembrittlement, discoloration, odor generation, stiffening, andsoftening, among others.

In particular, the deterioration of the performance of polymericmaterials and drugs due to e-beam radiation sterilization has beenassociated with free radical formation in a device during radiationexposure and by reaction with other parts of the polymer chains. Thereaction is dependent on e-beam dose and level of temperature.

Additionally, exposure to radiation, such as e-beam can cause a rise intemperature of an irradiated polymer sample. The rise in temperature isdependent on the level of exposure. It has been observed that astent-catheter assembly can increase about 7° C. per 12 kGy of radiationexposure. Mechanical properties of polymers are particularly sensitiveto changes in temperature. In particular, the effect on propertiesbecomes more profound as the temperature approaches and surpasses theglass transition temperature, Tg. It has been observed that e-beamradiation of polymer stents can result in cracking of struts duringdeployment due to onset of brittle behavior. The cracking can be due tothe increase in temperature, as well as the reduction in molecularweight. Additionally, the increase in temperature can result in a lossof some or all of the induced orientation and strength due to relaxationof polymer chains.

Furthermore, the increase in temperature can also increase the releaserate of drug resulting in a decrease of drug loading on a stent. Drugscan also degrade at increased temperatures during manufacture andstorage conditions, altering the total content and release rate of thedrug.

Therefore, the modification of polymer properties due to radiation isgenerally due the reactions which are chemical in nature as well as theincrease in temperature of a sample. Thus, it is believed that reducingthe temperature of a polymer-containing device before, during, and aftersterilization can slow down the rate of that the modification occurswhich can reduce or eliminate adverse affects of radiationsterilization.

In certain embodiments, a method of sterilizing a stent can includecooling a stent to a sterilization temperature (Ts) which is below anambient temperature prior to exposing the stent to radiation. Ambienttemperature can refer to a temperatures in a range between about 15° C.and 30° C. The cooled stent can then be exposed to a selected dose ofradiation from a radiation source.

The Ts can be, for example, less than ambient temperature, ambienttemperature, or the Tg of the polymer. In various embodiments, Ts can beless than 10° C., 0° C., −15° C., −25° C., −40° C., −70° C., −100° C.,−150° C., −200° C., −240° C., or less than −270° C.

The dose can be selected to be sufficient to sterilize the stent to adesired degree. As indicated above, the exposure can be in one or morepasses through a radiation source. In some embodiments, Ts can beselected so that the temperature of the stent after exposure toradiation is less than a selected temperature, for, example ambienttemperature, 40° C. below the Tg of the polymer, 20° C. below the Tg ofthe polymer, 10° C. below the Tg of the polymer, or the Tg of thepolymer.

In embodiments where the stent is sterilized in more than one passthrough a radiation source, the stent may be cooled prior to the firstpass, but not after the other passes. Alternatively, the stent can becooled after each pass or only after some of the passes. In cases inwhich the stent is cooled after a pass, the stent can be cooled to Ts,below Ts, or to a temperature between Ts and the temperature of thestent at the end of the pass.

The stent can be cooled to Ts prior to sterilization in a variety ofways, including, but not limited to, cooling the stent in a freezer,blowing a cold gas on the stent, placing the stent in proximity to acold medium such as ice, dry ice, freezable gel, liquid nitrogen, etc.Various particular embodiments of cooling a stent prior to sterilizationare described herein.

In certain embodiments, a stent an also be cooled during exposure toradiation sterilization. In one embodiment, the stent can be cooled sothat the temperature during sterilization, Tds, can be maintained at ornear the sterilization temperature, Ts. Alternatively, the stent can becooled so that Tds is maintained in a temperature or a range oftemperatures between Ts and the ambient temperature. Additionally, thestent can be cooled so that Tds is less than a temperature that is aboveambient temperature, for example, 40° C. below the Tg of the polymer,20° C. below the Tg of the polymer, 10° C. below the Tg of the polymer,or the Tg of the polymer.

A stent can be cooled during radiation sterilization by introducing acold medium into a radiation chamber, such as, but not limited to, coldair, nitrogen gas, liquid nitrogen, ice, a freezable gel, or dry ice.FIG. 2 depicts a radiation sterilization system 200 including aradiation chamber 205. Radiation chamber 205 has a radiation source 210for irradiating a stent 215 disposed on a support 220. A cooling fluidis conveyed into an inlet 225, as shown by an arrow 230. The coolingfluid can reduce and/or maintain the temperature of the stent below asterilization temperature. The cooling fluid can exit chamber 205through an outlet 235, as shown by an arrow 240. In addition to or as analternative to the cooling fluid, a cold medium 245, such as dry ice orice, can be disposed within chamber 205. Additionally or alternatively,the chamber can include a coil containing a circulating cooling fluidsuch as liquid nitrogen. Various other embodiments of cooling a stentduring radiation sterilization are disclosed herein.

In further embodiments, a stent can be disposed in a container orpackage having a cold medium incorporated into the container or package.The cold medium can cool or maintain a reduced temperature of the stentbefore, during, or after radiation sterilization. The cold medium canalso cool the stent during storage and transport of the stent. Thetemperature of the stent before, during, or after sterilization can bedifferent from the temperature during storage, Tstor. For example, Tstorcan be higher than a sterilization temperature.

Stents are typically sterilized, packaged, stored, and transported in a“ready to implant” configuration in which the stent is disposed at thedistal end of a catheter. FIG. 3 depicts a stent-catheter assembly 300with a stent 305 disposed on a distal end 310 of a catheter 315. Stent305 can be crimped over a balloon 320. The stent-catheter system 300 canbe packaged prior to or after radiation sterilization.

The throughput and efficiency of a radiation sterilization process canbe improved by locally or selectively cooling a stent. In general,selective cooling involves selectively cooling a stent and a smallregion around a stent rather than placing the stent in a large cooledenvironment such as a freezer. For example, the region can have adiameter less than the length of a stent, less than two times the lengthof a stent, less than four times the length of a stent, less than sixtimes the length of a stent, or less than 10 times the length of astent. The smaller mass of a stent allows the stent to be cooledrelatively quickly. The reduced temperature is also more easilymaintained by such selective or local cooling. Thus, selective coolingmakes a large freezer for handling a large production capacity of stentsunnecessary.

There are numerous ways of selectively cooling or reducing thetemperature of a stent. In one embodiment, a stent can be cooled to a Tsby selectively conveying a fluid at a reduced temperature at or adjacentto a stent. FIG. 4A depicts a stent 400 disposed on a catheter 405. Anozzle 410 blows a cold gas selectively at stent 400, as shown by anarrow 415. The cold gas can be, for example, air, nitrogen, argon, etc.The stent can be cooled to a Ts prior to sterilization or betweensterilization passes by the cold gas and then radiation sterilized. Thetemperature can be at a temperature at or below the Ts.

In an embodiment, as depicted in FIG. 4B, stent 400 can be inside of astorage container 420. The container, as describe below, can be a anyconvenient form, shape, and size to store a stent, for example, aflexible pouch made from a polymer, glass, ceramic, metallic substance,or a combination thereof. Nozzle 410 blows cold gas, as shown by anarrow 425, at container 420 where stent 400 is located.

In another embodiment, a stent can be disposed in a container that isapproximately large enough to store the stent. The container can be of asize that all or a majority of the catheter cannot fit inside of thecontainer. For example, the length and width of a container can be lessthan 15 times, 10 times, 7 times, 5 times, or, more narrowly, less than2 times the length of the stent. A cooling medium can be conveyed ordisposed in the container to reduce or maintain a temperature of thestent at a Ts.

After cooling the stent to the Ts, the stent can then be exposed toradiation to sterilize the stent. The cooled stent can be removed fromthe container and exposed to radiation or exposed to radiation whilewithin the container. FIG. 4C depicts a stent 430 disposed on a catheter435 positioned within a container 440. A cold gas is conveyed, as shownby an arrow 445, and circulated within, as shown by arrows 450,container 440. Container 4C can be made from metal, foam, plastic etc.Stent 430 can be exposed to radiation. In this case, it may be desirableto make the container from a material that can reduce the dose ofradiation received by the stent. The reduction in dose can be controlledby the thickness of the walls of the container. In addition, a materialcan be used that results in a more even distribution of radiation over agiven area. For example, a material with micro-voids, such as foam, orparticles can scatter e-beam radiation which results in the more evendistribution. “Foam” can refer to a polymer foam, for example,polystyrene foam such as Styrofoam from Dow Chemical Company, Midland,Mich. Thus, the container material can also be made of a material thatdistributes radiation more uniformly such as foam.

In certain embodiments, the dose of radiation received by a stent can beselectively reduced compared to the dose received by the entireassembly. The processing of a stent may introduce a lower level ofbioburden on the stent compared to the catheter. For example, the stentcan be protected by a sheath during certain processing steps. Therefore,the stent may require a lower dose or radiation to effectively sterilizethe stent. A reduced dose is advantageous since it will result in areduced modification of stent properties. Additionally, the uniformityof the dose received over a stent as compared to the entire assembly canalso be selectively increased.

In some embodiments, a radiation barrier can be selectively disposedbetween a stent cooled to a Ts and directed radiation. The barrier canselectively reduce the radiation exposure of the stent. The barrier canalso selectively increase the uniformity of the dose received over thestent. The barrier can be a material such as foam which is translucentto the directed radiation. For example, the wall of container 440 inFIG. 4C can selectively reduce the radiation from a radiation source andselectively increase the uniformity of radiation exposure within thecontainer.

In another embodiment, a stent on a stent-catheter assembly can beenclosed in a sheath during radiation sterilization. The barrier canselectively reduce the radiation exposure of the stent and increase theuniformity of the dose received over the stent. In some embodiments, thesheath can be enclosed in an additional layer of tubing to furtherreduce exposure and increase dose uniformity. The end of the sheath maybe designed to be closed to protect the stent from bioburden loading.Alternatively, the end may be open to allow for cooling of the stent. Inanother embodiment, a pocket can be disposed around the stent. Thesheath, tubing, or pocket can be composed of a polymer, metal, or acombination thereof.

Some embodiments of reduced temperature radiation sterilization caninclude a continuous process that allows one or more passes of radiationexposure. Such embodiments can incorporate selective cooling of thestent and selective reduction of radiation dose on the stent. FIGS. 5A-Cdepict an exemplary system 500 for radiation sterilization of stents.System 500 includes a hollow, ring-shaped conduit 505 that is adapted torotate, as shown by an arrow 510. Conduit 505 can be rotated, forexample, by a conveyer belt system (not shown). As conduit 505 rotatesit passes through a radiation chamber 515 that has a radiation source520 that can direct radiation onto conduit 505, as shown by an arrow522. Conduit 505 has an inlet 525 for a cooling gas which is conveyedinto conduit 505, as shown by an arrow 530.

Conduit 505 has a plurality of holes 540 along a top surface of conduit505. Holes 540 are in communication with a plurality of containers 545disposed within conduit 505. Holes 505 are of a size to accommodate acatheter and stent disposed on a catheter. FIG. 5B depicts a cutoutsection 550 from FIG. 5A showing the interior of conduit 505. FIG. 5Bshows a container 555 disposed within conduit 505. A distal end of acatheter 560 is disposed through hole 540 and within container 555. Thecontainer can be of a size that all or a majority of the catheter cannotfit inside of the container. A stent 565 is disposed on the distal endof catheter 560. FIG. 5C depicts a cross-sectional view down the axis ofconduit 505 showing container 555. The container can be made ofmaterials including, but not limited to, foam, metal, and plastics. Theconduit can be made of materials including, but not limited to, foam,metal, and plastics.

One more of sections with holes 540 can have a stent-catheter systemwith a stent 565 disposed within a container 555. As conduit 505rotates, a stent-catheter assembly is radiation sterilized as it passesthrough radiation chamber 525. Conduit 505 can rotate continuously at aconstant or near constant rate. Alternatively, conduit 505 can rotate indiscrete steps. Radiation source 520 directs radiation through container444 and onto stent 565. A plurality of stent-catheter assemblies can beradiation sterilized using system 500 as conduit 505 rotates. Astent-catheter assembly can be passed through radiation chamber 525 oneor more times. Additionally, the walls of conduit 555 can act as abarrier can selectively reduce the radiation exposure of the stent, asdescribed above.

During a radiation sterilization run, cooling gas circulates throughconduit 505 and cools stents 565. Therefore, stents 565 are cooled priorto, during, and after exposure to radiation in radiation chamber 515.The temperature of stents 565 can be maintained within a selected Tsrange. It is expected that the temperature of a stent 565 will be thegreatest immediately after exposure and the lowest just prior toexposure to radiation. The cooling of the stent can be adjusted so thatthe temperature of the stent just prior to exposure to radiation is at aselected Ts. The cooling of the stent can be adjusted by the flow rateof cooling gas, the temperature of the cooling gas, and the rate ofrotation of conduit 505.

FIG. 5D depicts an alternate embodiment for the interior of conduit 505.Interior cooling conduits 570 are positioned on either side of a stent565 disposed within conduit 505. A cooling fluid disposed within coolingconduits 570 selectively cools stent 565. The cooling fluid can be a gasor a liquid coolant such as liquid nitrogen.

Further embodiments of reduced temperature radiation sterilization of astent can include disposing a stent on or adjacent to a surface of acooling member such as a plate or slab. The cooling member can reduceand maintain a temperature of the stent at a Ts below ambienttemperature before, during, and/or after exposing the stent toradiation. The stent can be positioned between a radiation source andthe cooling member.

FIG. 6A depicts an exemplary embodiment a system 600 for reducedtemperature radiation sterilization of a stent. System 600 includes acooling slab or plate 605. A support 610 for supporting a stent isdisposed on the surface of cooling plate 605. A cooling medium withincooling plate 605 maintains the temperature of the surface of coolingplate 605 at a reduced temperature. Cooling plate 605 reduces andmaintains the temperature of a stent disposed on support 610 at areduced temperature prior to, during, and/or after radiationsterilization. Cooling plat 605 and support 610 can be made of metal,plastic, foam, etc.

A radiation source 615 directs radiation onto a stent, as shown by anarrow 620, disposed on support 610. Cooling plate 605 can be adapted totranslate in the direction shown by an arrow 625 so that a stentdisposed on support 610 is positioned beneath radiation source 615. Abarrier 630 can be positioned between radiation source 615 and the stentdisposed on support 610. Barrier 630 can be a foam or other materialsincluding metals and plastics, that distributes the radiation, such ase-beam, more uniformly so that there is a more uniform exposure on thestent and a catheter on which a stent is disposed. Additionally, barrier630 can also reduce the dose of the radiation directed from radiationsource 615.

Cooling plate 605 can be cooled by disposing a cooling medium withincooling plate 605. For example, FIGS. 6B-C depict the interior ofcooling plate 605 showing cooling coils 635 and 640, respectively. Acooling fluid enters coils 635 and 640, as shown by arrows 645 and 650.

FIG. 7 depicts a convection cooling system 700 in which a stent is atleast partially cooled by convection for radiation sterilization.Similar to system 600 in FIG. 6A, system 700 includes a cooling slab705, a support 710 for a stent to be sterilized, a barrier 730, and aradiation source 715 that directs radiation, as shown by an arrow 720.Cooling slab 705 has a cavity 735 of which a majority is filled with acooling medium 740. Cooling medium 740 can be, for example, dry ice,freezable gel, ice, or coils with a circulating fluid such as liquidnitrogen. A cooling gas, such as air, nitrogen, or argon, can be blowninto an inlet 745 to cavity 705. The temperature of the cooling gas isreduced as it circulates through and around cooling medium 740. Thereduced temperature cooling gas exits through a plurality of holes 750,as shown by arrows 755, and provides convection cooling of the stentdisposed on support 710. The stent is also partially cooled byconduction through cooling slab 705. The degree of cooling, and thus thetemperature of the stent can be adjusted by the flow rate of cooling gasand the temperature of cooling medium 740.

The exemplary embodiments in FIGS. 6A-C and 7 can also be adapted toselective cooling of the stent. FIG. 8 depicts a section 800 of conduit505 from FIG. 5A. A stent 805 is disposed on a catheter 810 disposedthrough hole 812 and within conduit 505. Conduit 505 has a cooling slab815 below stent 805. The interior of cooling slab 815 can have a coolingmedium as in FIG. 6B or 6C with coils that have a circulating coolingfluid. Alternatively, the cooling medium can be similar to FIG. 7 withcooling gas circulating, as shown by an arrow 820. The surface ofcooling slab 815 can have a plurality of holes 825 through which thecirculating cooling gas passes, as shown by arrows 830, which providesconvection cooling of stent 805.

The temperature of a stent stored at or near a selected sterilizationtemperature can increase in a relatively short period of time once it isremoved from a cold environment, such as a freezer. Because there isvery little mass and a high surface area in a stent-catheter assembly,it transitions from its cold state quickly. For example, a stent cantransition from −15° C. (freezer temperature) to 0° C. and higher withinminutes. Since there is typically set-up and loading time for radiationexposure after removal of a stent from a freezer, the temperature of thestent can increase substantially before exposure to radiation.

Thus, further embodiments of reduced temperature radiation sterilizationcan include systems and methods for cooling a stent disposed in astorage container. Stents or stent-catheter assemblies are typicallystored and transported in sealed storage containers. Such containers areadapted to protect the stent from environmental exposure (humidity,oxygen, light, etc.) which can have an adverse effect on the stent.

A storage container for a stent can be designed in any convenient formor shape that permits the effective enclosure of a stent containedtherein. The container, however, should be compact and shaped so as tominimize storage space occupied by the container. For example, withoutlimitation, the container can be in the shape of a tube, box or a pouch.In one commercially useful embodiment, container 210 can have arectangular cross-section with a width between 8 in and 12 in and alength between 10 in and 13 in. Also, depending on the types ofsubstance(s) used to construct the container, the container can be ofvarious degrees of rigidity or flexibility. The container can beconstructed of flexible films rather than rigid materials because it isless likely that the seal would be compromised by a change inatmospheric conditions during storage. For example, the container can beconstructed of two sheets or lamina which have been joined along anedge. Also, the container can be constructed of a single sheet or laminawhich has been folded and sealed along all edges or along all non-foldedges; or a bag or pocket which is sealed along one or more edges. Thepouches can be made from a polymer, glass, ceramic, metallic substance,or a combination thereof. Typically, the pouches are made of metallicfoil.

Such containers can be stored individually or stored together with otherpackaged stents. For example, a pouch can be disposed in a box, such aschipboard box. The chipboard box can then be stored individually oralong with a number of similar or identical containers including stents.

Embodiments of radiation sterilization of stents can include systems andmethods of cooling stents within the above-described or other storagecontainers. In some embodiments, a cooling medium can be incorporated orpositioned adjacent to the stent within a storage container. The systemcan be used to reduce and maintain a selected Ts of a stent prior to,during, and/or after radiation sterilization.

In some embodiments, a storage container including a stent can bedisposed within a cavity of an insulating material, such as foam. A coldmedium can be positioned adjacent to the storage container within thecavity to cool the stent. The cold medium or the container can bepositioned to maximize the cooling of the stent. The stent can besterilized by directing radiation from a radiation source in such a waythat the cold medium is not between the directed radiation and thestent.

FIG. 9A depicts an exemplary system 900 for reduced temperaturesterilization of a stent. System 900 includes stent-catheter assembly905 with a stent 910 attached to a distal end of a catheter 915 disposedwithin a container 920. Container 920 can be a chipboard box or othersuitable container. The stent-catheter assembly 905 can alternatively oradditionally be disposed within a sealed flexible container or pouchsuch as one described above. Container 920 is disposed within a cavityof a block 925 of an insulating material such as foam.

In addition, a cold medium 930 is positioned in a cavity within block925 adjacent to stent 910 to reduce and maintain the temperature ofstent 910 at a selected Ts. An additional cold medium (not shown) canalso be positioned on a side opposite to cold medium 930. Cold medium930 and an addition cold medium can be positioned to maximize cooling ofstent 910.

FIG. 9B depicts a cross-section of system 900 along an axis 935. FIG. 9Bshows cold medium 930 on one side of stent 910 and a cold medium 940 ona side opposite to stent 910. Radiation can be directed at stent 910 sothat a majority or all of radiation sterilizing the stent does not passthrough cold medium 930 or 940. Thus, a radiation-source can directradiation as shown by arrows 950 and 955. It is generally not desirableto direct radiation through cold medium 930 or 940 since the radiationcan be scattered, and thus may not effectively sterilize stent 910.Alternatively, as shown in FIG. 9C, system 900 can have one cold medium930 and no cold medium on a side opposite to stent 910. In this case,radiation can be directed as shown by an arrow 960.

System 900 can be passed through an e-beam chamber any number of timesto sterilize the stent. The cold media can be replaced as necessary.Such a system eliminates the need for freezing an entire product priorto processing and between radiation passes.

Additional embodiments of reduced temperature sterilization can includea cold medium incorporated in, coupled to, attached to, or associatedwith a storage container for a stein. The cold medium can be a freezablegel, ice pack, or other material can maintain a stent at or near aselected Ts. In some embodiments, the cold medium can be a material thatcan maintain a low temperature through endothermic reactions included inthe material. The cold medium can be positioned in or on the storagecontainer adjacent to the stent. A storage container with a cold mediumcan allow a stent to stay cold during transition states such as movingfrom the freezer to a radiation processing station and/or duringtransient heating during shipping.

FIG. 10A depicts a front view and FIG. 10B depicts an end view of astent catheter assembly 1000 including a stent 1005 disposed at thedistal end of a catheter 1010. Stent catheter assembly 1000 is disposedin a storage container 1015, as discussed above. Storage container 1015can be modified in various ways to incorporate a cold medium to reduceand maintain the stent temperature at or near a selected Ts.

FIG. 11A depicts an end view and FIG. 11B depicts a view at an angle ofa storage container 1100 modified to include a cold medium pocket 1105.Pocket 1105 can include a cold medium material that when cooled orfrozen can reduce and maintain stent 1005 at a reduced temperature.Pocket 1105 can incorporated into the structure of container 1100. Forexample, pocket 1100 can be thermoformed onto container 1100. Thus,pocket 1105 can be made of polymer materials. Pocket 1105 can also bemade of metallic materials.

Stent 1005 is disposed into container 1100 before or after the coldmedium pocket 1105 has been cooled or frozen. Stent 1005 can beradiation sterilized by directing radiation as shown by an arrow 1115.Additionally, container 1100 includes barrier layer 1117 including amaterial to reduce radiation exposure and/or increase the uniformity ofthe radiation directed at the stent. Barrier layer 1117 can be, forexample, foam or water.

FIG. 12A depicts an end view and FIG. 12B depicts a view at an angle ofa storage container 1200 modified to include a sleeve 1205 that isadapted to receive a cold medium pocket 1210, as shown by an arrow 1215.Cold medium pocket 1210 can be cooled or frozen separately fromcontainer 1200 and disposed into sleeve 1205 to cool stent 1005. Coldmedium pocket 1210 can be replaced as necessary prior to, aftersterilization, or between passes or radiation exposure. Stent 1005 canbe radiation sterilized by directing radiation as shown by an arrow1220. Container 1200 includes barrier layer 1225 including a material toreduce radiation exposure and/or increase the uniformity of theradiation directed at the stent.

FIG. 13A depicts an end view and FIG. 13B depicts a view at an angle ofa cold medium storage container 1300 that has a cold medium region 1305and a sleeve 1310 adapted to receive a stent storage container 1315.Cold medium storage container 1300 can be cooled or frozen separately ortogether with stent storage container 1315. Stent 1005 can be radiationsterilized by directing radiation as shown by an arrow 1320. Container1300 includes barrier layer 1325 including a material to reduceradiation exposure and/or increase the uniformity of the radiationdirected at the stent.

In some embodiments, a portion of barrier layer 1117, barrier layer1225, or barrier layer 1325 can be adapted to reduce exposure more thanthe rest of the barrier layer. For example, the portion can be thickeror be composed of a material that absorbs radiation to a greater degree.The portion can be of a size that allows selective increased reductionof radiation exposure of a stent. For example, the area of the portioncan be approximately that of an axial cross-section of a stent or two,four, or ten times the axial cross-section of a stent. The portion canselectively increase the reduction of the radiation exposure of thestent. The portion can also selectively enhance the increase in theuniformity of the dose received over the stent.

The “glass transition temperature,” Tg is the temperature at which theamorphous domains of a polymer change from a brittle vitreous state to asolid deformable or ductile state at atmospheric pressure. In otherwords, the Tg corresponds to the temperature where the onset ofsegmental motion in the chains of the polymer occurs. When an amorphousor semicrystalline polymer is exposed to an increasing temperature, thecoefficient of expansion and the heat capacity of the polymer bothincrease as the temperature is raised, indicating increased molecularmotion. As the temperature is raised the actual molecular volume in thesample remains constant, and so a higher coefficient of expansion pointsto an increase in free volume associated with the system and thereforeincreased freedom for the molecules to move. The increasing heatcapacity corresponds to an increase in heat dissipation throughmovement. Tg of a given polymer can be dependent on the heating rate andcan be influenced by the thermal history of the polymer. Furthermore,the chemical structure of the polymer heavily influences the glasstransition by affecting mobility.

The underlying structure or substrate of a stent can be completely or atleast in part made from a biodegradable polymer or combination ofbiodegradable polymers, a biostable polymer or combination of biostablepolymers, or a combination of biodegradable and biostable polymers.Additionally, a polymer-based coating for a surface of a device can be abiodegradable polymer or combination of biodegradable polymers, abiostable polymer or combination of biostable polymers, or a combinationof biodegradable and biostable polymers.

A polymer for use in fabricating an implantable medical device, such asa stent, can be biostable, bioabsorbable, biodegradable or bioerodable.Biostable refers to polymers that are not biodegradable. The termsbiodegradable, bioabsorbable, and bioerodable are used interchangeablyand refer to polymers that are capable of being completely degradedand/or eroded when exposed to bodily fluids such as blood and can begradually resorbed, absorbed and/or eliminated by the body. Theprocesses of breaking down and absorption of the polymer can be causedby, for example, hydrolysis and metabolic processes.

It is understood that after the process of degradation, erosion,absorption, and/or resorption has been completed, no part of the stentwill remain or in the case of coating applications on a biostablescaffolding, no polymer will remain on the device. In some embodiments,very negligible traces or residue may be left behind. For stents madefrom a biodegradable polymer, the stent is intended to remain in thebody for a duration of time until its intended function of, for example,maintaining vascular patency and/or drug delivery is accomplished.

Representative examples of polymers that may be used to fabricate asubstrate of an implantable medical device or a coating for animplantable medical device include, but are not limited to,poly(N-acetylglucosamine) (Chitin), Chitosan, poly(hydroxyvalerate),poly(lactide-co-glycolide), poly(hydroxybutyrate),poly(hydroxybutyrate-co-valerate), polyorthoester, polyanhydride,poly(glycolic acid), poly(glycolide), poly(L-lactic acid),poly(L-lactide), poly(D,L-lactic acid), poly(L-lactide-co-glycolide);poly(D,L-lactide), poly(caprolactone), poly(trimethylene carbonate),polyethylene amide, polyethylene acrylate, poly(glycolicacid-co-trimethylene carbonate), co-poly(ether-esters) (e.g. PEO/PLA),polyphosphazenes, biomolecules (such as fibrin, fibrinogen, cellulose,starch, collagen and hyaluronic acid), polyurethanes, silicones,polyesters, polyolefins, polyisobutylene and ethylene-alphaolefincopolymers, acrylic polymers and copolymers other than polyacrylates,vinyl halide polymers and copolymers (such as polyvinyl chloride),polyvinyl ethers (such as polyvinyl methyl ether), polyvinylidenehalides (such as polyvinylidene chloride), polyacrylonitrile, polyvinylketones, polyvinyl aromatics (such as polystyrene), polyvinyl esters(such as polyvinyl acetate), acrylonitrile-styrene copolymers, ABSresins, polyamides (such as Nylon 66 and polycaprolactam),polycarbonates, polyoxymethylenes, polyimides, polyethers,polyurethanes, rayon, rayon-triacetate, cellulose, cellulose acetate,cellulose butyrate, cellulose acetate butyrate, cellophane, cellulosenitrate, cellulose propionate, cellulose ethers, and carboxymethylcellulose.

Additional representative examples of polymers that may be especiallywell suited for use in fabricating an implantable medical deviceaccording to the methods disclosed herein include ethylene vinyl alcoholcopolymer (commonly known by the generic name EVOH or by the trade nameEVAL), poly(butyl methacrylate), poly(vinylidenefluoride-co-hexafluororpropene) (e.g., SOLEF 21508, available fromSolvay Solexis PVDF, Thorofare, N.J.), polyvinylidene fluoride(otherwise known as KYNAR, available from ATOFINA Chemicals,Philadelphia, Pa.), ethylene-vinyl acetate copolymers, and polyethyleneglycol.

A non-polymer substrate of the device may be made of a metallic materialor an alloy such as, but not limited to, cobalt chromium alloy(ELGILOY), stainless steel (316L), high nitrogen stainless steel, e.g.,BIODUR 108, cobalt chrome alloy L-605, “MP35N,” “MP20N,” ELASTINITE(Nitinol), tantalum, nickel-titanium alloy, platinum-iridium alloy,gold, magnesium, or combinations thereof “MP35N” and “MP20N” are tradenames for alloys of cobalt, nickel, chromium and molybdenum availablefrom Standard Press Steel Co., Jenkintown, Pa. “MP35N” consists of 35%cobalt, 35% nickel, 20% chromium, and 10% molybdenum. “MP20N” consistsof 50% cobalt, 20% nickel, 20% chromium, and 10% molybdenum.

A drug or active agent can include, but is not limited to, any substancecapable of exerting a therapeutic, prophylactic, or diagnostic effect.The drugs for use in the implantable medical device, such as a stent ornon-load bearing scaffolding structure may be of any or a combination ofa therapeutic, prophylactic, or diagnostic agent. Examples of activeagents include antiproliferative substances such as actinomycin D, orderivatives and analogs thereof (manufactured by Sigma-Aldrich 1001 WestSaint Paul Avenue, Milwaukee, Wis. 53233; or COSMEGEN available fromMerck). Synonyms of actinomycin D include dactinomycin, actinomycin IV,actinomycin I₁, actinomycin X₁, and actinomycin C₁. The bioactive agentcan also fall under the genus of antineoplastic, anti-inflammatory,antiplatelet, anticoagulant, antifibrin, antithrombin, antimitotic,antibiotic, antiallergic and antioxidant substances. Examples of suchantineoplastics and/or antimitotics include paclitaxel, (e.g., TAXOL® byBristol-Myers Squibb Co., Stamford, Conn.), docetaxel (e.g., Taxotere®,from Aventis S.A., Frankfurt, Germany), methotrexate, azathioprine,vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g.,Adriamycin® from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g.,Mutamycin® from Bristol-Myers Squibb Co., Stamford, Conn.). Examples ofsuch antiplatelets, anticoagulants, antifibrin, and antithrombinsinclude aspirin, sodium heparin, low molecular weight heparins,heparinoids, hirudin, argatroban, forskolin, vapiprost, prostacyclin andprostacyclin analogues, dextran, D-phe-pro-arg-chloromethylketone(synthetic antithrombin), dipyridamole, glycoprotein IIb/IIIa plateletmembrane receptor antagonist antibody, recombinant hirudin, and thrombininhibitors such as Angiomax ä (Biogen, Inc., Cambridge, Mass.). Examplesof such cytostatic or antiproliferative agents include angiopeptin,angiotensin converting enzyme inhibitors such as captopril (e.g.,Capoten® and Capozide® from Bristol-Myers Squibb Co., Stamford, Conn.),cilazapril or lisinopril (e.g., Prinivil® and Prinzide® from Merck &Co., Inc., Whitehouse Station, N.J.), calcium channel blockers (such asnifedipine), colchicine, proteins, peptides, fibroblast growth factor(FGF) antagonists, fish oil (omega 3-fatty acid), histamine antagonists,lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol loweringdrug, brand name Mevacor® from Merck & Co., Inc., Whitehouse Station,N.J.), monoclonal antibodies (such as those specific forPlatelet-Derived Growth Factor (PDGF) receptors), nitroprusside,phosphodiesterase inhibitors, prostaglandin inhibitors, suramin,serotonin blockers, steroids, thioprotease inhibitors,triazolopyrimidine (a PDGF antagonist), and nitric oxide. An example ofan antiallergic agent is permirolast potassium. Other therapeuticsubstances or agents which may be appropriate agents include cisplatin,insulin sensitizers, receptor tyrosine kinase inhibitors, carboplatin,alpha-interferon, genetically engineered epithelial cells, steroidalanti-inflammatory agents, non-steroidal anti-inflammatory agents,antivirals, anticancer drugs, anticoagulant agents, free radicalscavengers, estradiol, antibiotics, nitric oxide donors, super oxidedismutases, super oxide dismutases mimics,4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),tacrolimus, dexamethasone, ABT-578, clobetasol, cytostatic agents,prodrugs thereof, co-drugs thereof, and a combination thereof. Othertherapeutic substances or agents may include rapamycin and structuralderivatives or functional analogs thereof, such as40-O-(2-hydroxy)ethyl-rapamycin (known by the trade name of EVEROLIMUS),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, methyl rapamycin, and40-O-tetrazole-rapamycin.

A stent storage container, for example, container 1015, can be made ofvarious substances that form a barrier when sealed. For instance, thecan be made of a polymer, glass, ceramic or a metallic substance such asaluminum, stainless steel or gold. If made of a metallic substance, thecontainer for example can be formed of a metallic film. Suitableexamples of films include, but are not limited to, gold, platinum,platinum/iridium alloy, tantalum, palladium, chromium, and aluminum.Suitable materials for the container may also include oxides of theabove-mentioned metals, for example, aluminum oxide. Medical storagecontainers may be obtained from, for example, Oliver Products Company ofGrand Rapids, Mich.

Suitable polymers for construction of a stent storage container caninclude polymers of polyolefins, polyurethanes, cellulosics (i.e.,polymers having mer units derived from cellulose), polyesters,polyamides, poly(hexamethylene isophthalamide/terephthalamide)(commercially available as Selar PA™), poly(ethyleneterephthalate-co-p-oxybenzoate) (PET/PHB, e.g., copolymer having about60-80 mole percent PHB), poly(hydroxy amide ethers), polyacrylates,polyacrylonitrile, acrylonitrile/styrene copolymer (commerciallyavailable as Lopac™), rubber-modified acrylonitrile/acrylate copolymer(commercially available as Barex™), liquid crystal polymers (LCP) (e.g.Vectra™ available from Hoescht-Celanese, Zenite™ available from DuPont,and Xydar™ available from Amoco Performance Chemicals), poly(phenylenesulfide), polystyrenes, polypropylenes, polycarbonates, epoxies composedof bisphenol A based diepoxides with amine cure, aliphatic polyketones(e.g., Carilon™ available from Shell, and Ketonex™ available fromBritish Petroleum), polysulfones, poly(estersulfone),poly(urethane-sulfone), poly(carbonate-sulfone), poly(3-hydroxyoxetane),poly(amino ethers), gelatin, amylose, parylene-C, parylene-D, andparylene-N.

Representative polyolefins include those based upon alpha-monoolefinmonomers having from about 2 to 6 carbon atoms and halogen substitutedolefins, i.e., halogenated polyolefins. By way of example, and notlimitation, low to high density polyethylenes, essentially unplasticizedpoly(vinyl chloride), poly(vinylidene chloride) (Saran™), poly(vinylfluoride), poly(vinylidene fluoride), poly(tetrafluoroethylene)(Teflon), poly(chlorotrifluoroethylene) (Kel-F™), and mixtures thereofare suitable. Low to high density polyethylenes are generally understoodto have densities of about 0.92 g cm⁻³ to about 0.96 g cm⁻³, however, nobright line can be drawn for density classifications and the density canvary according to the supplier.

Representative polyurethanes include polyurethanes having a glasstransition temperature above a storage or ambient temperature, forexample having a glass transition temperature of at least 40° C. to 60°C., or having a non-polar soft segment which includes a hydrocarbon,silicone, fluorosilicone, or mixtures thereof. For example, Elast-Eon™,manufactured by Elastomedic/CSIRO Molecular Science, is a polyurethanewith a non-polar soft segment which is made from 1,4-butanediol,4,4′-methylenediphenyl diisocyanate, and a soft segment composed of ablend of poly(hexamethylene oxide) (PHMO) andbishydroxyethoxypropylpolydimethylsiloxane (PDMS). A useful example hasa blend of 20% by weight PHMO and 80% by weight PDMS.

Representative examples of cellulosics include, but are not limited to,cellulose acetate having a degree of substitution (DS) greater thanabout 0.8 or less than about 0.6, ethyl cellulose, cellulose nitrate,cellulose acetate butyrate, methyl cellulose, and mixtures thereof.

Representative polyesters include saturated or unsaturated polyesterssuch as, but not limited to, poly(butylene terephthalate), poly(ethylene2,6-naphthalene dicarboxylate) (PEN), and poly(ethylene terephthalate).

Representative polyamides include crystalline or amorphous polyamidessuch as, but not limited to, nylon-6, nylon-6,6, nylon-6,9, nylon-6,10,nylon-11, aromatic nylon MXD6 (manufactured by Mitsubishi Gas ChemicalAmerica, Inc.), and mixtures thereof.

Representative polyacrylates include, but are not limited to,poly(methylmethacrylate) and polymethacrylate.

A stent storage container may also be composed of copolymers of vinylmonomers with each other and olefins such as poly(ethyl vinyl acetate).

Examples

The examples and experimental data set forth below are for illustrativepurposes only and are in no way meant to limit the invention. Thefollowing examples are given to aid in understanding the invention, butit is to be understood that the invention is not limited to theparticular materials or procedures of examples.

The benefits of cooling a stent prior to e-beam sterilization areillustrated by the following examples. The effect of a reducedtemperature e-beam radiation treatment on the number of cracks upondeployment of a poly(L-lactide) stent was investigated.

Five stent samples were radiation sterilized with e-beam radiation. Thestent samples were 1.3 mm outside diameter. After radiationsterilization, each sample was then deployed or expanded to 3.5 mm. Thenumber of cracks above 25% of the strut width and the total number ofcracks at day 1 and day 7 after deployment were then counted. Fourdifferent samples were compared as shown in Table 1.

TABLE 1 Summary of samples irradiated with e-beam. Number of Sample Dose(kGy) Passes Temperature (° C.) 1 25 1 −15 2 25 2 −15 3 25 2 RoomTemperature 4 40 3 −15 5 40 1 Room Temperature

FIG. 14 depicts the number of cracks above 25% of the strut width foreach of the samples at day 1 and day 7. The temperature refers to thetemperature of the sample prior to e-beam sterilization. Samples 1, 2,and 4 were cooled to −15° C. prior to sterilization. The cooled sampleswere not cooled during or after sterilization.

Regarding samples with 25 kGy doses, the number of cracks above 25% ofstrut width at day 1 for the reduced temperature e-beam samples, 1 and2, is about the same as the room temperature sterilization. However, thenumber of cracks at day 7 was substantially larger for the roomtemperature samples.

With respect to samples with 40 kGy doses, the number of cracks above25% of strut width for the room temperature sample was substantiallylarger than the reduced temperature sample at both day 1 and day 7.Therefore, reduced temperature radiation sterilization substantiallyreduces the number of cracks in a deployed stent.

In addition, the influence of a reduced temperature e-beam radiationtreatment on drug recovery was investigated. As indicated above,radiation sterilization can cause a loss of drug from a drug-containingstent. The loss can result from premature release or thermaldegradation. Stent samples with a drug-polymer coating were radiationsterilized with e-beam radiation. The samples had a poly(L-lactide)substrate with a poly(DL-lactide)-drug coating. The drug was everolimus.The radiation dose was 25 kGy and the temperature of the samples wasreduced to −15° C. prior to radiation exposure. The mass of the coatingand amount of drug on each sample before sterilization was determined byweighing the stent samples before and after coating. The amount of drugremaining after e-beam sterilization was determined by dissolving theremaining coating in a solvent and using High Performance LiquidChromotography to determine the amount of drug remaining. Table 2 showsthe results of the drug recovery for a set of samples that haveundergone reduced temperature e-beam and room temperature e-beamsterilization. The average recovery for the reduced temperature e-beamwas 94.79% and 85.72% for the room temperature e-beam. Therefore, thereduced temperature improves drug delivery during e-beam sterilization.

TABLE 2 Drug recovery after e-beam sterilization. Reduced TemperatureE-Beam Coating weight (μg) Drug Recovery (μg) 216 93.07 218 95.04 21496.81 217 95.47 217 93.58 Ave. 94.79 Standard Deviation 1.5 % RSD 1.59Room Temperature E-Beam Coating weight (μg) Drug Recovery (%) 212 88.05214 76.68 202 90.38 208 89.74 218 83.75 Ave. 85.72 Standard Deviation5.68 % RSD 6.62

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects.

1-46. (canceled)
 47. A method for sterilizing a stent comprising:disposing a stent-catheter assembly on or adjacent to a surface of acooling member, the stent-catheter assembly including a stent; placing abarrier between at least the stent and a radiation source; and directinga dose of radiation at the stent; wherein the cooling member maintains atemperature of the stent at or near a sterilization temperature belowambient temperature and the barrier is configured to increase theuniformity of dose received by at least the stent and/or to reduce thedose received by at least the stent.
 48. The method of claim 47, whereinthe barrier is made from a material having micro-voids or particlesarranged to scatter radiation to provide a more uniform distribution ofdose.
 49. The method of claim 47, wherein the cooling member comprises aslab with a cooling fluid circulating within the slab.
 50. The method ofclaim 47, wherein the stent is a polymer stent comprising a biostablepolymer, biodegradable polymer, or a combination thereof.
 51. The methodof claim 47, wherein the stent comprises a coating including a biostablepolymer, biodegradable polymer, drug, or a combination thereof.
 52. Asystem for sterilizing a stent-catheter assembly, the stent-catheterassembly including a stent, comprising: a cooling source; a barrierconfigured for scattering radiation to thereby produce a more uniformdose distribution; and a radiation source; wherein the system isarranged so that at least the stent is to be located adjacent thecooling source and the barrier is disposed between the stent and theradiation source.
 53. The system of claim 52, wherein the stent islocated adjacent the cooling source and the barrier is disposed betweenthe stent and the radiation source.
 54. The system of claim 52, whereinthe stent is a polymer stent comprising a biostable polymer,biodegradable polymer, or a combination thereof.
 55. The system of claim52, wherein the stent comprises a coating including a biostable polymer,biodegradable polymer, drug, or a combination thereof. 56-61. (canceled)62. The system of claim 52, the cooling source further including acooling medium disposed in a cavity of a cooling member, the surface ofthe cooling member having a plurality of holes in communication with thecavity, the holes for conveying a cooling fluid from the surface of thecooling member, the cooling fluid facilitating maintaining a temperatureof the stent at or near the sterilization temperature. 63-65. (canceled)66. The system of claim 52, further including a storage containerconfigured to hold the stent, the storage container being disposedwithin a cavity of a body of thermal insulating material; wherein thecooling source is disposed adjacent to the storage container within thecavity.
 67. (canceled)
 68. The system of claim 66, further comprising asecond cooling source positioned in the cavity adjacent to the stent ona side opposite to the first cooling source.
 69. The system of claim 66,wherein the cooling source is selected from the group comprising ice,dry ice, and a freezable gel. 70-71. (canceled)
 72. The system of claim66, wherein the thermal insulating material comprises foam insulation.73. The method of claim 47, further including the step of disposing astorage container containing the stent within a cavity of a body of athermal insulating material, wherein the cooling source is within, or influid communication with the cavity.
 74. The method of claim 73, whereinthe radiation is directed so that the radiation exposing the stent doesnot pass through the cooling source.
 75. The method of claim 73, whereinthe cooling source and the stent are positioned so that the coolingsource is not between the directed radiation and the stent.
 76. Themethod of claim 73, wherein the stent is a polymer stent comprising abiostable polymer, biodegradable polymer, or a combination thereof. 77.(canceled)
 78. A system for sterilizing a stent comprising: a containerfor holding a stent-catheter assembly including a polymer stent, whereinthe container is capable of being sealed along an edge thereof, thecontainer including on a first side thereof, a barrier configured toscatter radiation, and on a second side thereof, a cavity; wherein thesystem is configured for sterilizing the stent-catheter assembly at asterilization temperature maintained by a cooling member received in thecavity, and wherein when the stent is exposed to radiation the barrieris disposed between a radiation source and the stent so as to increasethe uniformity of dose received by the stent.
 79. The system of claim78, further comprising a radiation source adjacent the container forexposing the stent to radiation for sterilization of the stent.
 80. Thesystem of claim 78, wherein the cavity comprises a thermoform pocket.81. The system of claim 78, wherein the cavity is formed by a sleeveattached to the container.
 82. The system of claim 78, wherein thecooling source is selected from the group consisting of ice, dry ice,and a freezable gel.
 83. A method of sterilizing of a stent comprising:providing a stent in a sealed container, the sealed container having atone side a barrier for scattering radiation and at another side a cavityfor holding a cooling member, the cooling member being arranged relativeto the stent to maintain at least the stent at a sterilizationtemperature; and directing radiation at the container such that theradiation passes through the barrier before reaching the container.84-87. (canceled)